Preparation method of gadoxetate disodium

Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a preparation method of gadoxetate disodium. According to the invention, the purity of the prepared final product is greater than 99.5% and the maximum single impurity is less than 0.1% by adjusting the existing production process of the gadoxetate disodium, so that the pharmaceutical grade quality standard is met. Column chromatography purification is not adopted in the whole production process, so that the production cost is reduced, and the production period is shortened; meanwhile, each step of the process is simple, convenient and controllable to operate, the production condition is mild, special equipment is not needed, the process safety and the operation convenience are greatly improved, the core bottleneck of industrial application of the existing process is effectively solved, a reliable scheme is provided for large-scale efficient production of the gadoxetate disodium, and the process has important industrial application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for preparing gadoxetate disodium. Background Technology

[0002] Gadolinium-based contrast agents are currently the most widely used contrast agents for magnetic resonance imaging (MRI). They enhance image contrast, helping doctors to more clearly observe the structure of organs and tissues within the body, playing a crucial role in diagnosing various diseases. Disodium gadoxetate is a highly specific MRI contrast agent for the liver, with the structural formula shown below. Compared to other MRI contrast agents, it can improve the detection rate and accuracy of qualitative diagnosis of focal liver lesions, especially showing advantages in the detection and differential diagnosis of small lesions.

[0003]

[0004] Currently, the main route for obtaining disodium gadoxetate is as follows: using N-Boc-L-tyrosine methyl ester (compound 1) as a raw material, it is reduced by sodium borohydride to generate compound 2. Compound 2 is activated by methanesulfonyl chloride, and then reacted with 1,2-ethylenediamine to generate compound 3. Compound 3 is de-Boced by concentrated hydrochloric acid or hydrogen chloride to generate compound 4. Compound 4 is alkylated with tert-butyl bromoacetate to generate compound 5. Compound 5 is hydrolyzed by sodium hydroxide to generate compound 6. Compound 6 is salted with gadolinium oxide to obtain disodium gadoxetate. The reaction route is as follows.

[0005]

[0006] However, the existing synthetic route still has some technical problems: In step one, sodium borohydride needs to be added in batches, which is not only cumbersome to operate, but also makes the solid material susceptible to moisture absorption during the addition process, resulting in poor process controllability and hindering stable large-scale production; in step two, methanesulfonyl chloride is a highly toxic chemical under strict control, and the procurement process is cumbersome, making it unsuitable for industrial production; in steps two and three, the amine ester exchange reaction is prone to producing dimer impurities, and compounds 3 and 4 are difficult to remove by conventional purification methods, affecting the quality of subsequent intermediates and disodium gadoxetate; in steps four and five, the alkylation reaction is incomplete, requiring excessive use of tert-butyl bromoacetate, and compound 6 is difficult to remove residual reagents by conventional purification methods, resulting in poor quality of disodium gadoxetate.

[0007] Therefore, it is of great significance to develop a preparation process that is more suitable for industrialization and has better product quality control. Summary of the Invention

[0008] To address the aforementioned problems in existing processes for preparing disodium gadoxetate, this invention provides a method for preparing disodium gadoxetate.

[0009] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows: A method for preparing disodium gadoxetate includes the following steps: Step 1: N-BOC-L-tyrosine methyl ester (compound 1) and the reducing agent are added to the first solvent at once and mixed thoroughly. Then, the second solvent is slowly added to carry out the reduction reaction to obtain compound 2. The reaction route is as follows: ; The reducing agent is at least one of sodium borohydride, potassium borohydride, lithium aluminum hydride, borane tetrahydrofuran, sodium triacetoxyborohydride, or borane dimethyl sulfide; the first solvent is at least one of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, or dichloromethane; and the second solvent is at least one of methanol, ethanol, or isopropanol.

[0010] In existing technologies, due to the vigorous reduction reaction in this step, the reducing agent is usually added in batches, which is cumbersome and makes it difficult to control the solid feeding rate, easily leading to process instability and making it unsuitable for large-scale industrial production. The inventors, through creative thinking, discovered that by adding the reducing agent all at once to the first solvent, and confirming by TLC monitoring that the reaction had not yet occurred, and then slowly adding the second solvent to the system, the reaction can be smoothly started and proceed slowly. This effectively solves the core problems of vigorous reaction and complex operation in existing technologies, improves process controllability, and is more suitable for the needs of large-scale industrial production. In one specific embodiment of the present invention, the second solvent can be added using a peristaltic pump, or other commonly used tools in the art capable of slow addition; the present invention does not impose any particular limitation. This addition method not only improves the controllability and repeatability of the process, but also reduces reliance on manual labor, which is conducive to achieving more efficient production operations.

[0011] Preferably, in step one, the addition rate of the second solvent is controlled to be 0.1 L / min-5 L / min.

[0012] Preferably, the reducing agent is sodium borohydride, the first solvent is tetrahydrofuran, and the second solvent is methanol.

[0013] Preferably, in step one, the reduction reaction temperature is 0℃~50℃ and the reaction time is 1h~5h.

[0014] More preferably, in step one, the reduction reaction is carried out at a temperature of 20°C to 30°C for 3 hours.

[0015] It should be noted that in step one, after the reduction reaction is completed, the following steps are also included: concentrating the reaction solution, adding water to the concentrated residue, extracting with ethyl acetate, adding a crystallization solvent to the extract to crystallize, separating the solid and liquid, drying, and obtaining compound 2.

[0016] Specifically, in step one, the volume-to-mass ratio of ethyl acetate to N-BOC-L-tyrosine methyl ester is (1~5) mL:1g, preferably 2 mL:1g.

[0017] Specifically, the crystallization solvent is at least one of n-hexane, petroleum ether, or n-heptane, preferably n-hexane.

[0018] Specifically, in step one, the volume-to-mass ratio of the crystallization solvent to N-BOC-L-tyrosine methyl ester is (10~25) mL:1g, preferably 18 mL:1g.

[0019] Furthermore, the method for preparing the disodium gadoxetate further includes the following steps: Step 2: Compound 2 is activated by hydroxyl group reaction with methanesulfonic anhydride, and then subjected to amine transesterification reaction with ethylenediamine to obtain compound 3. The reaction equation is as follows.

[0020]

[0021] In existing technologies, methanesulfonyl chloride is used as a hydroxyl activator. This invention uses methanesulfonic anhydride instead of methanesulfonyl chloride. Methanesulfonic anhydride is not a specially controlled highly toxic chemical, making the procurement process simpler and more suitable for the practical application needs of large-scale industrial production. At the same time, methanesulfonic anhydride has excellent hydroxyl activation reactivity and selectivity, which can efficiently achieve the activation and conversion of the target hydroxyl group. While ensuring the smooth progress of the reaction, it helps to improve the yield and purity of the product, thereby effectively overcoming the problem of limited industrial application caused by the use of methanesulfonyl chloride in existing technologies.

[0022] Preferably, in step two, the organic solvent is tetrahydrofuran.

[0023] Preferably, in step two, the molar ratio of methanesulfonic anhydride to compound 2 is 1.1:1 to 1.5:1.

[0024] More preferably, in step two, the molar ratio of methanesulfonic anhydride to compound 2 is 1.3:1.

[0025] Preferably, in step two, the temperature of the hydroxyl activation reaction is 0℃~30℃, and the reaction time is 0.5h~3h.

[0026] More preferably, in step two, the temperature of the hydroxyl activation reaction is 0℃~10℃, and the reaction time is 0.5h.

[0027] Preferably, in step two, the molar ratio of ethylenediamine to compound 2 is 15:1 to 30:1.

[0028] More preferably, in step two, the molar ratio of ethylenediamine to compound 2 is 25:1.

[0029] Preferably, in step two, the temperature of the amine-ester exchange reaction is 40℃~70℃, and the reaction time is 0.5h~5h.

[0030] More preferably, in step two, the temperature of the amine-ester exchange reaction is 60°C to 70°C, and the reaction time is 1h to 2h.

[0031] As a specific embodiment of the present invention, step two specifically includes: Compound 2 was added to an organic solvent and stirred to dissolve. Triethylamine was added, and the temperature was lowered to -5℃ to 10℃. Methanesulfonic anhydride was slowly added. After the addition was complete, the mixture was stirred at 10℃ to 20℃ for 0.5h to 1h. Then ethylenediamine was added, and the temperature was raised to 60℃ to 70℃ and stirred for 1h to 2h. The reaction solution was concentrated while maintaining the temperature below 60℃. Water was added to the concentrated residue, and the mixture was extracted with ethyl acetate. The extract was then concentrated to obtain compound 3.

[0032] Furthermore, the preparation method of disodium gadoxetate also includes: Step 3: After de-Boc reaction of compound 3, crude product of compound 4 as shown in formula (Ⅲ) is obtained; the crude product of compound 4 is added to a mixed solution of methanol and ethyl acetate, and the temperature of the system is gradually reduced from 50℃~60℃ to 15℃~30℃ in a multi-stage cooling process to induce crystallization, thereby obtaining purified product of compound 4; wherein at least two intermediate temperature plateaus are set in the multi-stage cooling process; the reaction equation is as follows:

[0033] In existing technologies, when ethylenediamine is used as a reactant, the highly reactive amino groups of compound 3 generated in the reaction readily react with compound 2 to form a dimer impurity. Even with optimization of process parameters such as reactant ratios, reaction temperature, and reaction time, the formation of this dimer impurity cannot be avoided and can only be removed through subsequent purification. However, because this dimer has similar structural active groups and small polarity differences to compound 4, conventional purification methods are difficult to effectively separate it. As a result, the residual dimer impurity in compound 4 continues to participate in subsequent reactions, ultimately affecting the quality of subsequent intermediates and disodium gadoxetate, becoming a key issue restricting the industrial application of this synthetic route.

[0034] This invention creatively discovers that recrystallizing compound 4 using a methanol / ethyl acetate system, and employing a gradient crystallization method during the crystallization process, can achieve highly efficient removal of dimer impurities. After treatment by this method, the content of dimer impurities decreased from 2.5% to below 0.2%, and the content of other individual impurities was all less than 0.1%, with the total impurity content below 0.5%, while the reaction yield remained above 90%.

[0035] This technical solution has multiple advantages: First, it eliminates the need to replace ethylenediamine with N-boc, effectively reducing production costs; second, it avoids the potential genotoxic impurities that may be introduced during resin purification, improving product safety; third, it avoids the problem of treating large amounts of inorganic salt wastewater generated during resin regeneration, making it more environmentally friendly; and fourth, recrystallization, as a mature and reliable purification method in industrial production, can significantly improve the stability of the production process, thereby ensuring the quality consistency of subsequent intermediates and the final product, disodium gadoxetate.

[0036] Preferably, in step three, the volume ratio of methanol to ethyl acetate is 3:(0.5~1).

[0037] Preferably, in step three, the volume-to-mass ratio of methanol to compound 4 is (2~5) mL:1g.

[0038] Preferably, in step three, the specific steps of the multi-stage cooling process include: adding the crude product of compound 4 to methanol, heating to 60℃~65℃ to dissolve, then slowly adding ethyl acetate, mixing evenly, cooling to 50℃~60℃, stirring for 0.5h~2h, then cooling to 40℃~50℃, stirring for 0.5h~2h, continuing to cool to 30℃~40℃, stirring for 0.5h~2h, and finally cooling to 15℃~30℃, stirring for 0.5h~2h to obtain the purified product of compound 4.

[0039] By controlling the temperature and time of each stage of cooling and crystallization, the crystal growth rate and lattice structure can be precisely controlled, so that the target compound 4 gradually forms a crystal with a regular structure and uniform purity. Impurities such as dimers, due to their polarity differences and insufficient lattice compatibility, are difficult to embed into the target crystal structure and are effectively excluded from the crystal, thus achieving efficient separation of impurities and target products.

[0040] As a specific embodiment of the present invention, the step of compound 3 undergoing the deBoc reaction specifically includes: Compound 3 was added to an alcohol solvent and stirred to dissolve. An ethyl acetate solution of hydrochloric acid was slowly added at 20°C to 30°C. After the addition was complete, the temperature was raised to 60°C to 65°C and the reaction was stirred for 3 to 5 hours. The temperature was then lowered to 15°C to 20°C and crystallization was allowed to occur for 1 to 2 hours. The solid and liquid were separated and washed with ethyl acetate to obtain the crude product of compound 4.

[0041] Furthermore, the method for preparing the disodium gadoxetate further includes: Step 4: Under acid-binding agent conditions, compound 4 is subjected to a substitution reaction with tert-butyl bromoacetate. After the reaction is completed, a small molecule organic amine is added to the reaction solution to quench the reaction. The reaction solution is concentrated, and ethyl acetate is added to the concentrated residue for extraction. The organic phase is concentrated to obtain compound 5 as shown in formula (Ⅳ). Wherein, the small molecule organic amine is a primary or secondary amine with ≤4 carbon atoms. Step 5: Under alkaline conditions, compound 5 is hydrolyzed in an alcohol solvent. After the reaction is complete, the mixture is cooled to crystallize, yielding compound 6 as shown in formula (V). The reaction equation is as follows.

[0042]

[0043] Compound 5, prepared using methods found in existing literature, is oily with a purity of only about 85%, and its purification and subsequent derivatization face numerous technical bottlenecks. In current techniques, the purification of compound 5 relies on column chromatography. After purification, compound 5 needs to be hydrolyzed in a mixture of alcohol and water to prepare compound 6. If the purification step of compound 5 is omitted and the hydrolysis reaction is carried out directly, compound 6 will not crystallize properly. Because the sodium salt of compound 6 is highly soluble, the product can only be separated by concentrating the reaction aqueous solution to dryness. However, this operation has significant drawbacks: the long concentration process results in substantial energy waste, reduces production efficiency, and the final compound 6 is of poor quality, with a purity of only about 92%. Gadoxetate disodium prepared from compound 6 of this quality cannot meet pharmaceutical-grade quality standards.

[0044] After the reaction of compound 5 is completed, this invention adds a small-molecule organic amine quenching reaction step in the post-processing stage. Using this process, the quality of compound 5 is significantly improved, with its purity increasing dramatically from 85% to 97%. Simultaneously, compound 5 purified by this optimized process exhibits a significant advantage in the preparation of compound 6: the sodium salt of compound 6, generated by its hydrolysis, can crystallize normally in the alcohol / water reaction system, increasing the product purity from 92% to 99.8%. This purity level fully ensures that the final product, disodium gadoxetate, meets pharmaceutical standards.

[0045] Preferably, in step four, the small molecule organic amine is at least one of methylamine, dimethylamine, ethylamine, diethylamine, ethanolamine, diethanolamine, or ethylenediamine.

[0046] More preferably, in step four, the small molecule organic amine is diethylamine.

[0047] These small-molecule organic amines have moderate amine group activity, which can quickly react with excess tert-butyl bromoacetate in the system, capturing residual active ester reagents and avoiding subsequent side reactions with compound 5 or reaction intermediates; at the same time, they will not react with the target product compound 5 due to excessive activity, thus ensuring the activity of fully quenched tert-butyl bromoacetate and avoiding interference with the target product, laying the core foundation for improving the purity of compound 5.

[0048] Preferably, in step four, the amount of the small molecule organic amine added is 5% to 20% of the mass of tert-butyl bromoacetate.

[0049] Preferably, in step four, the molar ratio of tert-butyl bromoacetate to compound 5 is 5:1 to 9:1, more preferably 6:1 to 7:1.

[0050] Preferably, in step four, the acid-binding agent is potassium carbonate.

[0051] Preferably, in step four, the temperature of the substitution reaction is 50℃~70℃, and the reaction time is 10h~20h.

[0052] It should be noted that after adding the small molecule organic amine, the mixture should be stirred at 50℃~70℃ for 2h~3h to fully quench the activity of tert-butyl bromoacetate.

[0053] It should be noted that the organic phase is washed with a saturated sodium chloride aqueous solution before the concentrated residue is added to the ethyl acetate for extraction.

[0054] Preferably, in step five, the alcohol solvent is at least one of methanol, ethanol, or isopropanol, with methanol being preferred.

[0055] Preferably, in step five, the temperature of the hydrolysis reaction is 40℃~70℃, and the reaction time is 3h~10h.

[0056] Preferably, in step five, the hydrolysis reaction is carried out at a temperature of 60°C to 70°C for 7 hours.

[0057] Preferably, in step five, the cooling and crystallization temperature is 20℃~50℃, and the crystallization time is 1h~3h.

[0058] More preferably, in step five, the cooling and crystallization temperature is 25°C to 35°C, and the crystallization time is 1 hour.

[0059] Furthermore, the method for preparing the disodium gadoxetate further includes: Step 6: Compound 6 is extracted with an organic solvent under acidic conditions. The resulting aqueous phase is reacted with gadolinium oxide to form a salt. After the reaction is complete, the pH is adjusted to neutral, activated carbon is added for adsorption, solid-liquid separation is performed, the resulting liquid phase is concentrated, and a mixed solution of anhydrous ethanol, acetone and water is added to the concentrated residue. The mixture is cooled to crystallize and obtain disodium gadoxetate. The reaction equation is shown below.

[0060]

[0061] As a specific embodiment of the present invention, the step of organic solvent extraction of compound 6 under acidic conditions specifically includes: Compound 6 was dissolved in water and extracted with an organic solvent. The resulting aqueous phase was passed through a strongly acidic cation exchange resin to adjust the pH to 5-6, filtered, and the filtrate was extracted with an organic solvent. The resulting aqueous phase was then passed through a strongly acidic cation exchange resin to adjust the pH to 3-3.5, filtered, and the filtrate was extracted with an organic solvent. The organic phase was discarded, and the resulting aqueous phase was reacted with gadolinium oxide to form a salt.

[0062] Before adding gadolinium oxide, the aqueous solution of compound 6 is pretreated by extraction with organic solvents at different pH values ​​to remove small molecule amines or some less polar impurities. This prevents small molecule compounds from remaining in the final product and affecting product quality. Existing technologies often use a mixture of water and ethanol to purify compound 6, resulting in low purification yields. In this invention, acetone is added to the purification solvent, increasing the product yield from 85% to 95% and achieving a product purity of over 99.7%, significantly improving the purification effect of compound 6.

[0063] Specifically, the organic solvent used for extraction is ethyl acetate, dichloromethane, methyl tert-butyl ether, or isopropyl acetate, with ethyl acetate being preferred.

[0064] Preferably, in step six, the organic solvent is at least one of ethyl acetate, dichloromethane, methyl tert-butyl ether, or isopropyl acetate.

[0065] Preferably, in step six, the temperature of the salt formation reaction is 80℃~100℃, and the reaction time is 2h~5h.

[0066] More preferably, in step six, the temperature of the salt formation reaction is 90℃~100℃, and the reaction time is 3h.

[0067] Preferably, in step six, the volume-to-mass ratio of water, anhydrous ethanol, acetone and compound 6 is 1 mL: (1~5) mL: (5~10) mL: 1 g.

[0068] Preferably, in step six, the temperature for cooling and crystallization is 0℃~30℃, and the crystallization time is 1h~3h.

[0069] More preferably, in step six, the cooling and crystallization temperature is 20°C to 30°C, and the crystallization time is 1 hour.

[0070] The method for preparing gadoxetate disodium provided by this invention, through adjustments to the existing production process, yields a final product with a purity greater than 99.5% and a maximum single impurity of less than 0.1%, meeting pharmaceutical-grade quality standards. Furthermore, the entire production process does not employ column chromatography purification, reducing production costs and shortening the production cycle. Simultaneously, each step of the process is simple and controllable, with mild production conditions requiring no special equipment, significantly improving process safety and ease of operation. This effectively solves the core bottleneck of existing processes for industrial application, providing a reliable solution for the large-scale, efficient production of gadoxetate disodium, and possesses significant industrial application value. Detailed Implementation

[0071] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0072] To better illustrate the present invention, further examples are provided below.

[0073] Unless otherwise specified, the chemical reagents and apparatus used in the following examples are commercially available.

[0074] Example 1 This embodiment provides a method for preparing compound 2, the specific steps of which are as follows: Add 5L of tetrahydrofuran to a 20L reactor, add 0.47kg of sodium borohydride and 2.0kg of compound 1 at a controlled temperature of 10℃~30℃, stir until dissolved, and slowly add 6L of methanol at a controlled temperature of 10℃~30℃. After the addition is complete, react at a controlled temperature of 20℃~30℃ for 3 hours, concentrate at a controlled temperature below 50℃ until no obvious liquid flows out, and continue to concentrate for 1 hour. Add 4L of purified water to the concentrated residue, extract with 4L of ethyl acetate, combine the organic phases, and slowly add 36L of n-hexane. After the addition is complete, stir for 1 hour, filter, wash the filter cake with 2L of n-hexane, and dry the filter cake under vacuum at 40℃~50℃ to obtain compound 2 with a yield of 97% and a purity of 99.5%.

[0075]

[0076] Example 2 This embodiment provides a method for preparing compound 4, comprising the following steps: Add 6 L of tetrahydrofuran and 1.5 kg of compound 2 to a 20 L reactor. Stir until dissolved while maintaining the temperature at 10 °C to 30 °C. Then add 0.92 kg of triethylamine. After the addition is complete, cool to -5 °C to 10 °C and slowly add 1.15 kg of methanesulfonic anhydride while maintaining the temperature at -5 °C to 10 °C. After the addition is complete, maintain the temperature at 0 °C to 10 °C and stir for 0.5 h. Then add 30.83 g of ethylenediamine. After the addition is complete, heat to 60 °C to 65 °C and stir for 1 h. Maintain the temperature below 60 °C and concentrate the reaction solution under reduced pressure until no obvious liquid flows out. Continue to concentrate for 1 h. Then add 9 L of purified water to the concentrated residue and extract twice with ethyl acetate, 9 L each time. Combine the organic phases and wash three times with 1.5 L of purified water. Discard the aqueous phase. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure while maintaining the temperature below 50 °C until no obvious liquid flows out. Continue to concentrate for 1 h to obtain compound 3.

[0077] Add 6 L of methanol to compound 3, stir at 30℃~50℃ until dissolved, cool to 20℃~30℃, slowly add 6.3 L of 4M HCl in ethyl acetate solution, after which heat to 60℃~65℃, maintain the temperature at 60℃~65℃ and stir for 3 h, cool to 15℃~20℃ to crystallize for 1 h, filter, wash the filter cake with 1.5 L of ethyl acetate to obtain crude compound 4.

[0078] The crude compound 4 was added to 4.5 L of methanol, heated to 60-65 °C and stirred for 1 h. Then, 1.5 L of ethyl acetate was slowly added. After the addition was complete, the temperature was slowly lowered to 50-60 °C to crystallize for 1 h. The temperature was then slowly lowered to 40-50 °C to crystallize for 1 h, then slowly lowered to 30-40 °C to crystallize for 1 h, and finally slowly lowered to 15-25 °C to crystallize for 1 h. The mixture was filtered, and the filter cake was washed with 1.5 L of ethyl acetate. The filter cake was then vacuum dried at 40-50 °C to obtain compound 4 with a yield of 92.1%, a purity of 99.7%, and a dimer impurity of 0.15%.

[0079]

[0080] The detection method for dimer impurities is as follows: Chromatographic column: Shim-pack Gws 4.6*250mm, 5μm, C18; Column temperature: 30℃, wavelength: 225nm, flow rate: 0.5ml / min, injection volume: 10μL; Running time: 50 minutes; Mobile phase A: 0.05% perchloric acid solution (measure 2000 mL of purified water, add 4 mL of perchloric acid precisely, mix well, and filter to obtain the solution); Mobile phase B: Acetonitrile; Gradient elution, the elution order is as follows:

[0081] Comparative Example 1 The only difference between this comparative example and Example 2 is that the refining solvent for the crude compound 4 is replaced with methanol. The specific steps are as follows: The crude compound 4 was added to 6 L of methanol, heated to 60℃~65℃ and stirred for 1 h, then slowly cooled to 50℃~60℃ to crystallize for 1 h, then slowly cooled to 40℃~50℃ to crystallize for 1 h, then slowly cooled to 30℃~40℃ to crystallize for 1 h, and finally slowly cooled to 15℃~25℃ to crystallize for 1 h. The mixture was filtered, and the filter cake was washed with 1.5 L of ethyl acetate. The filter cake was then dried under vacuum at 40℃~50℃ to obtain compound 4, with a yield of 70.1%, a purity of 99.5%, and a dimer impurity of 0.12%.

[0082] The methanol was replaced with anhydrous ethanol, and the crude compound 4 was purified using the same method. The final yield of compound 4 was 93.8%, the purity was 98.0%, and the dimer impurity was 1.5%.

[0083] The methanol was replaced with ethyl acetate, and the crude compound 4 was purified using the same method. The final yield of compound 4 was 95.6%, the purity was 97.8%, and the dimer impurity was 2.0%.

[0084] Comparative Example 2 The only difference between this comparative example and Example 2 is that the refining solvent for the crude compound 4 is replaced with a mixed solution of methanol and water at a volume ratio of 3:0.5. The specific steps are as follows: The crude compound 4 was added to 4.5 L of methanol, heated to 60℃~65℃ and stirred for 1 h. Then, 1.5 L of purified water was slowly added. After the addition was complete, the temperature was slowly lowered to 50℃~60℃ to crystallize for 1 h. The temperature was then slowly lowered to 40℃~50℃ to crystallize for 1 h. The temperature was then slowly lowered to 30℃~40℃ to crystallize for 1 h. Finally, the temperature was slowly lowered to 15℃~25℃ to crystallize for 1 h. It was found that no solid precipitated in the end.

[0085] Comparative Example 3 The only difference between this comparative example and Example 2 is that the refining solvent for the crude compound 4 is replaced with a mixed solution of anhydrous ethanol and water in a volume ratio of 3:0.5. The specific steps are as follows: The crude compound 4 was added to 4.5 L of anhydrous ethanol, heated to 60℃~65℃ and stirred for 1 h. Then, 1.5 L of purified water was slowly added. After the addition was complete, the temperature was slowly lowered to 50℃~60℃ to crystallize for 1 h. The temperature was then slowly lowered to 40℃~50℃ to crystallize for 1 h. The temperature was then slowly lowered to 30℃~40℃ to crystallize for 1 h. Finally, the temperature was slowly lowered to 15℃~25℃ to crystallize for 1 h. It was found that no solid precipitated in the end.

[0086] Comparative Example 4 The only difference between this comparative example and Example 2 is that the refining solvent for the crude compound 4 is replaced with a mixed solution of anhydrous ethanol and ethyl acetate in a volume ratio of 3:0.5. The specific steps are as follows: The crude compound 4 was added to 4.5 L of anhydrous ethanol, heated to 60-65 °C and stirred for 1 h. Then, 1.5 L of ethyl acetate was slowly added. After the addition was complete, the temperature was slowly lowered to 50-60 °C to crystallize for 1 h. The temperature was then slowly lowered to 40-50 °C to crystallize for 1 h, then slowly lowered to 30-40 °C to crystallize for 1 h, and finally slowly lowered to 15-25 °C to crystallize for 1 h. The mixture was filtered, and the filter cake was washed with 1.5 L of ethyl acetate. The filter cake was then vacuum dried at 40-50 °C to obtain compound 4, with a yield of 94.2%, a purity of 97.9%, and a dimer impurity of 1.8%.

[0087] Comparative Example 5 The only difference between this comparative example and Example 2 is that the gradient cooling method of Example 2 is replaced with a single cooling method. The specific steps are as follows: The crude compound 4 was added to 4.5 L of methanol, heated to 60 °C~65 °C and stirred for 1 h. Then, 1.5 L of ethyl acetate was slowly added. After the addition was complete, the temperature was lowered to 15 °C~25 °C to allow crystallization for 4 h. The mixture was filtered, and the filter cake was washed with 1.5 L of ethyl acetate. The filter cake was dried under vacuum at 40 °C~50 °C to obtain compound 4 with a yield of 90.2%, a purity of 99.16%, and a dimer impurity of 0.73%.

[0088] Comparative Example 6 The only difference between this comparative example and Example 2 is the gradient cooling method. The specific steps are as follows: The crude compound 4 was added to 4.5 L of methanol, heated to 60 °C~65 °C and stirred for 1 h. Then, 1.5 L of ethyl acetate was slowly added. After the addition was complete, the temperature was slowly lowered to 40 °C~50 °C to crystallize for 2 h. Then, the temperature was slowly lowered to 15 °C~25 °C to crystallize for 2 h. The mixture was filtered, and the filter cake was washed with 1.5 L of ethyl acetate. The filter cake was dried under vacuum at 40 °C~50 °C to obtain compound 4 with a yield of 92.0%, a purity of 99.25%, and a dimer impurity of 0.57%.

[0089] Example 3 This embodiment provides a method for preparing compound 6, comprising the following steps: Add 20 L of tetrahydrofuran and 1.0 kg of compound 4 to a 50 L reactor and stir until dissolved. Then add an aqueous solution of potassium carbonate (21.9 kg of potassium carbonate and 1.5 L of purified water). After the addition is complete, slowly add 3.38 kg of tert-butyl bromoacetate. After the addition is complete, heat to 60℃~70℃ and stir for 20 h. Then add 0.3 kg of diethylamine and react at 60℃~70℃ for 2 h. Cool down to 20℃~30℃, filter, and concentrate the filtrate under reduced pressure at a temperature below 60℃ until no obvious liquid flows out. Continue to concentrate for 1 h. Then add 5 L of saturated sodium chloride aqueous solution to the concentrated residue for washing. Extract three times with ethyl acetate, 5 L each time. Combine the organic phases and wash the organic phase with 10 L of saturated sodium chloride aqueous solution. Discard the aqueous phase. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure at a temperature below 50℃ until no obvious liquid flows out. Continue to concentrate for 1 h to obtain compound 5.

[0090] 10 L of methanol was added to compound 5 and stirred at 30 °C to 40 °C until dissolved. Then, an aqueous solution of sodium hydroxide (1.04 kg of sodium hydroxide and 1 L of purified water) was slowly added. After the addition was complete, the temperature was raised to 60 °C to 70 °C and stirred for 3 h. The temperature was then lowered to 25 °C to 35 °C and stirred for 1 h. The mixture was filtered, and the filter cake was washed with 1 L of methanol. The filter cake was then dried under vacuum at 40 °C to 50 °C to obtain compound 6 with a yield of 90% and a purity of 99.2%.

[0091]

[0092] Comparative Example 7 The only difference between this comparative example and Example 3 is that the quenching operation is not performed; all other steps are exactly the same. The specific steps are as follows: Add 20L of tetrahydrofuran and 1.0kg of compound 4 to a 50L reactor and stir until dissolved. Then add potassium carbonate aqueous solution (21.9kg potassium carbonate and 1.5L purified water). After the addition is complete, slowly add 3.38kg of tert-butyl bromoacetate. After the addition is complete, heat to 60℃~70℃ and stir for 20h. Cool to 20℃~30℃, filter, and concentrate the filtrate under reduced pressure at a temperature below 60℃ until no obvious liquid flows out. Continue to concentrate for 1h. Then add 5L of saturated sodium chloride aqueous solution to the concentrated residue for washing. Extract three times with ethyl acetate, 5L each time. Combine the organic phases and wash the organic phase with 10L of saturated sodium chloride aqueous solution. Discard the aqueous phase. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure at a temperature below 50℃ until no obvious liquid flows out. Continue to concentrate for 1h to obtain compound 5.

[0093] Compound 6 was prepared by the same method as in Example 3, with a yield of 91.3% and a purity of 95.2%.

[0094] Example 4 This embodiment provides a method for preparing compound 6, which differs from Example 3 only in that ethylenediamine is replaced with an equal amount of methylamine, dimethylamine, ethylamine, ethanolamine, diethanolamine, or diethylamine. The rest is exactly the same and will not be described again here.

[0095] The yield and purity of compound 6 prepared according to the same method as in Example 3 are shown in Table 1.

[0096] Table 1

[0097] Comparative Example 10 The only difference between this comparative example and Example 3 is that the quencher ethylenediamine is replaced with triethylamine or tripropylamine; otherwise, they are exactly the same and will not be described again here.

[0098] The yield and purity of compound 6 prepared according to the same method as in Example 3 are shown in Table 2.

[0099] Table 2

[0100] Example 5 This embodiment provides a method for preparing disodium gadoxetate, comprising the following steps: Add 1.0 kg of compound 6 and 7.5 kg of purified water to a 20 L reactor, stir until dissolved, and extract twice with ethyl acetate, 3 L each time. Discard the organic phase. Adjust the pH of the aqueous phase to 5-6 using a strong acid anion exchange resin, filter, and extract the filtrate twice with ethyl acetate, 3 L each time. Discard the organic phase. Adjust the pH of the aqueous phase to 3.0-3.5 using a strong acid anion exchange resin. After adjustment, filter, and extract the filtrate twice with ethyl acetate, 3 L each time. Discard the organic phase. Add 0.28 kg of gadolinium oxide to the aqueous phase. After addition, heat to 90 °C. The reaction was carried out at 100℃ for 3 hours, then cooled to room temperature. The pH was adjusted to 6.8-7.2 with 10% sodium hydroxide. After adjustment, the filtrate was concentrated until no obvious liquid flowed out, while maintaining the external temperature below 60℃. Concentration was continued for 2 hours. 1L of purified water was added to the concentrated residue, and 5L of ethanol was slowly added while stirring. Then, 10L of acetone was slowly added. The temperature was maintained at 20℃-30℃ and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with 2L of acetone. The filter cake was then vacuum dried at 40℃-50℃ to obtain disodium gadoxetate with a yield of 95%, a purity of 99.5%, and a maximum single impurity of less than 0.1%.

[0101] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing disodium gadoxetate, characterized in that, Includes the following steps: Step 1: Add N-BOC-L-tyrosine methyl ester and reducing agent to the first solvent at once, mix well, and then slowly add the second solvent to carry out the reduction reaction to obtain compound 2 as shown in formula (Ⅰ); ； The reducing agent is at least one of sodium borohydride, potassium borohydride, lithium aluminum hydride, borane tetrahydrofuran, sodium triacetoxyborohydride, or borane dimethyl sulfide; the first solvent is at least one of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, or dichloromethane; and the second solvent is at least one of methanol, ethanol, or isopropanol.

2. The method for preparing disodium gadoxetate as described in claim 1, characterized in that, In step one, the reducing agent is sodium borohydride, the first solvent is tetrahydrofuran, and the second solvent is methanol; and / or In step one, the reduction reaction is carried out at a temperature of 0°C to 50°C for 1 hour to 5 hours.

3. The method for preparing disodium gadoxetate as described in claim 1, characterized in that, Also includes: Step 2: Compound 2 is activated by hydroxyl group reaction with methanesulfonic anhydride, and then subjected to amine transesterification reaction with ethylenediamine to obtain compound 3 as shown in formula (II); 。 4. The method for preparing disodium gadoxetate as described in claim 3, characterized in that, In step two, the molar ratio of methanesulfonic anhydride to compound 2 is 1.1:1 to 1.5:1; and / or In step two, the temperature of the hydroxyl activation reaction is 0℃~30℃, and the reaction time is 0.5h~3h; and / or In step two, the molar ratio of ethylenediamine to compound 2 is 15:1 to 30:1; and / or In step two, the temperature of the amine-ester exchange reaction is 40℃~70℃, and the reaction time is 0.5h~5h.

5. The method for preparing disodium gadoxetate as described in claim 3, characterized in that, Also includes: Step 3: After de-Boc reaction of compound 3, crude product of compound 4 as shown in formula (Ⅲ) is obtained; The crude product of compound 4 was added to a mixed solution of methanol and ethyl acetate, and the system temperature was gradually reduced from 50°C to 60°C to 15°C to 30°C in a multi-stage cooling process to induce crystallization and obtain the refined product of compound 4; wherein at least two intermediate temperature plateaus were set in the multi-stage cooling process. 。 6. The method for preparing disodium gadoxetate as described in claim 5, characterized in that, In step three, the volume ratio of methanol to ethyl acetate is 3:(0.5~1); and / or In step three, the volume-to-mass ratio of methanol to compound 4 is (2~5) mL:1 g; and / or In step three, the specific steps of the multi-stage cooling process include: adding the crude product of compound 4 to methanol, heating to 60℃~65℃ to dissolve, then slowly adding ethyl acetate, mixing evenly, cooling to 50℃~60℃, stirring for 0.5h~2h, then cooling to 40℃~50℃, stirring for 0.5h~2h, continuing to cool to 30℃~40℃, stirring for 0.5h~2h, and finally cooling to 15℃~30℃, stirring for 0.5h~2h to obtain the purified product of compound 4.

7. The method for preparing disodium gadoxetate as described in claim 5, characterized in that, Also includes: Step 4: Under acid-binding agent conditions, compound 4 is subjected to a substitution reaction with tert-butyl bromoacetate. After the reaction is completed, a small molecule organic amine is added to the reaction solution to quench the reaction. The reaction solution is concentrated, and ethyl acetate is added to the concentrated residue for extraction. The organic phase is concentrated to obtain compound 5 as shown in formula (Ⅳ). Wherein, the small molecule organic amine is a primary or secondary amine with ≤4 carbon atoms. Step 5: Under alkaline conditions, compound 5 is hydrolyzed in an alcohol solvent. After the reaction is complete, the mixture is cooled to crystallize, yielding compound 6 as shown in formula (V). 。 8. The method for preparing disodium gadoxetate as described in claim 7, characterized in that, In step four, the small molecule organic amine is at least one selected from methylamine, dimethylamine, ethylamine, diethylamine, ethanolamine, diethanolamine, or ethylenediamine; and / or In step four, the substitution reaction is carried out at a temperature of 50°C to 70°C for a reaction time of 10 to 20 hours; and / or In step five, the alcohol solvent is at least one of methanol, ethanol, or isopropanol; and / or In step five, the hydrolysis reaction is carried out at a temperature of 40℃ to 70℃ for a reaction time of 3h to 10h; and / or In step five, the temperature for cooling and crystallization is 20℃~50℃.

9. The method for preparing disodium gadoxetate as described in claim 7, characterized in that, Also includes: Step 6: Extract compound 6 with an organic solvent under acidic conditions. React the resulting aqueous phase with gadolinium oxide to form a salt. After the reaction is complete, adjust the pH to neutral, add activated carbon for adsorption, separate the solid and liquid phases, concentrate the resulting liquid phase, add a mixed solution of anhydrous ethanol, acetone and water to the concentrated residue, cool and crystallize to obtain disodium gadoxetate.

10. The method for preparing disodium gadoxetate as described in claim 9, characterized in that, In step six, the organic solvent is at least one selected from ethyl acetate, dichloromethane, methyl tert-butyl ether, or isopropyl acetate; and / or In step six, the salt-forming reaction is carried out at a temperature of 80℃~100℃ for a reaction time of 2h~5h; and / or In step six, the volume-to-mass ratio of water, anhydrous ethanol, acetone, and compound 6 is 1 mL:(1~5) mL:(5~10) mL:1 g; and / or In step six, the temperature for cooling and crystallization is 0℃~30℃, and the crystallization time is 1h~3h.

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